Throughout this application various publications are referenced, many in parenthesis. Full citations for these publications are provided at the end of the Detailed Description. The disclosures of these publications in their entireties are hereby incorporated by reference in this application.
Acute tissue rejection can be observed in two major clinical situations: 1) blood transfusions; and 2) organ transplantation. In both situations, to be described in greater detail below, antibody binding and complement fixation are the two major mechanisms underlying the destruction of the donor tissue (the donor tissue referring to blood or organs). Previous means of attempting to control acute rejection have centered on tissue matching and pharmacologic interventions. Despite these measures a significant number of often life-threatening acute tissue rejection reactions continue to occur.
Blood transfusions are a crucial component in the treatment of a number of acute and chronic medical problems. These range from massive blood loss following traumatic injury to chronic transfusions in diseases such as thalassemia and sickle cell anemia. In most acute injuries simple blood typing (ABO/rh) is sufficient to identify appropriate donors. Occasionally, however, rare blood types are encountered where an appropriate match cannot be quickly found, a situation which may be life-threatening. More often problems are encountered in individuals, usually minorities, receiving chronic transfusions (e.g., as in sickle cell anemia and the thalassemias). Often simple blood typing becomes insufficient in determining a proper match because these individuals develop transfusion reactions to minor red blood cell antigens. The transfusion reactions to these minor red blood cell antigens can make it nearly impossible to identify appropriate blood donors (Vichinsky et al. 1990).
To date, the only solutions to the above situations are to store autologous blood (frozen or at 4.degree. C.), keep a blood bank registry of potential donors with rare blood types, and to encourage minority blood donations. While all of these steps are prudent and variably effective, situations still arise where an appropriate (or even satisfactory) blood match cannot be made. Therefore, a need exists for methods and agents which will disguise otherwise immunogenic (or directly immunologically recognizable) red blood cells.
Similarly, the transplantation of organs (such as kidneys and livers) from one human to another is often made difficult by a lack of exact immunologic identity between donor and recipient. Sometimes, the transplanted organ is subject to direct attack by the immune system of the recipient even before a secondary immunologic response has had time to occur. This so-called `hyperacute rejection` is often life threatening and, obviously, prevents the effective integration of the transplant into the recipient. Therefore, a need exists for methods and agents which may prevent immediate recognition of the endothelial surfaces of organ transplants, thereby moderating or stopping the process of acute graft rejection. In a similar vein, the transplantation of organs from one species to another (`xenotransplant`) faces even more formidable immunologic barriers and would be greatly facilitated by methods for blocking immunologic recognition of the foreign endothelial surface.
Proteins have been modified by the covalent attachment of soluble polymers such as polyvinyl alcohol, carboxymethyl cellulose (Mitz and Summaria 1961), and polyvinylpyrrolidone (von Specht et al. 1973). Various antigenic purified proteins have also been modified by covalent attachment of polyethylene glycols (PEGs) to render the resulting proteins non-immunogenic. Abuchowski et al. (1977a) disclose the modification of purified bovine serum albumin (BSA) by covalent attachment of methoxypolyethylene glycol, rendering the BSA non-immunogenic. Abuchowski et al. (1977b) disclose the modification of purified bovine liver catalase by covalent attachment of methoxypolyethylene glycol, rendering the catalase non-immunogenic. Jackson et al. (1987) disclose the modification of purified ovalbumin with monomethoxypolyethylene glycol using cyanuric chloride as a coupling agent. The resulting ovalbumin is non-immunogenic.
Various reports have also shown that polyethylene glycol (PEG) coated liposomes have improved circulation time (Klivanov et al. 1991; Senior et al. 1991; Maruyama et al. 1992; and Lasic 1992).
Islet of Langerhans have been microencapsulated in semipermeable membranes in order to decrease immunogenicity of implanted islets (Lacy et al. 1991; Lim 1980). Sawhney et al. (1994) coated rat islets with a polyethylene glycol tetraarylate hydrogel. Importantly, PEG was not directly incorporated into the islet cell membranes but rather the cells were surrounded by the PEG-containing hydrogel.
Zalipsky and Lee (1992) discuss the use of functionalized polyethylene glycols for modification of polypeptides, while Merrill (1992) and Park and Wan Kim (1992) both relate to protein modification with polyethylene oxide.
U.S. Pat. No. 4,179,337 of Davis et al. discloses purified polypeptides, such as enzymes and insulin, which are coupled to polyethylene glycol or polypropylene glycol having a molecular weight of 500 to 20,000 daltons to provide a physiologically active non-immunogenic water soluble polypeptide composition. The polyethylene glycol or polypropylene glycol protect the polypeptide from loss of activity and the composition can be injected into the mammalian circulatory system with substantially no immunogenic response.
U.S. Pat. No. 5,006,333 of Saifer et al. discloses a biologically persistent, water-soluble, substantially non-immunogenic, substantially non-antigenic conjugate of superoxide dismutase, prepared by coupling purified superoxide dismutase to one to five strands of a polyalkylene glycol which is polyethylene glycol or polyethylene-polypropylene glycol copolymer, wherein the polyalkylene glycol has an average molecular weight of about 35,000-1,000,000.
U.S. Pat. No. 5,013,556 of Woodle et al. discloses a liposome composition which contains between 1-20 mole percent of an amphipathic lipid derivatized with a polyalkylether, as exemplified by phosphatidylethanolamine derivatized with polyethylene glycol.
U.S. Pat. No. 5,214,131 of Sano et al. discloses a polyethylene glycol derivative, a purified peptide modified by the polyethylene glycol derivative, and a method for production thereof. The polyethylene glycol derivative is capable of modifying the guanidino groups in peptides. The peptides modified by the polyethylene glycol derivative are extremely stable, are considerably delayed in biological clearance, and exhibit their physiological activities effectively over a long period.
A need continues to exist for methods of making entire cells and tissues and organs, as opposed to purified proteins or peptides, non-immunogenic.